Total Blood Protein
Total blood protein refers to the combined concentration of all proteins found in the fluid component of blood, known as plasma. These proteins are fundamental biological molecules that perform a vast array of critical functions throughout the body. The two primary categories measured are albumin and globulins. Albumin, synthesized in the liver, is the most abundant plasma protein and is essential for maintaining osmotic pressure, preventing fluid leakage from blood vessels, and transporting various substances, including hormones, fatty acids, and medications. Globulins comprise a diverse group, including antibodies (immunoglobulins) vital for immune defense, transport proteins that carry lipids and metal ions, and clotting factors necessary for blood coagulation. Collectively, these proteins are indispensable for maintaining physiological balance, ensuring robust immune responses, and facilitating nutrient and waste transport within the circulatory system.
The of total blood protein is a routine and significant diagnostic test in clinical practice. Deviations from normal ranges can signal a variety of underlying health conditions. Low total blood protein levels (hypoproteinemia) may indicate issues such as malnutrition, severe liver dysfunction (due to impaired protein synthesis), kidney disease (leading to excessive protein loss through urine), or malabsorption disorders where the body struggles to absorb nutrients. Conversely, elevated total blood protein levels (hyperproteinemia) can suggest conditions like dehydration, chronic inflammation, certain autoimmune diseases, or specific types of cancer such, as multiple myeloma, which involves the overproduction of certain immune proteins. Monitoring these levels provides crucial insights into a person’s nutritional status, organ function, and the presence of inflammatory or immune system disorders, thereby guiding subsequent diagnostic investigations and therapeutic interventions.
Understanding the factors that influence total blood protein levels, including genetic predispositions, carries substantial implications for both medical practice and public health. While total blood protein is a composite measure, the individual levels of its constituent proteins can be significantly affected by genetic variations. Research into protein quantitative trait loci (pQTLs) has identified specific genetic regions, often involving single nucleotide polymorphisms (SNPs), that are associated with variations in the concentrations of particular proteins. For example, studies have linked specific SNPs, such asrs11574783 and rs2170436 , to parathyroid hormone levels, andrs1880887 to alkaline phosphatase levels. Furthermore, SNPs within theABO gene, like rs8176746 and rs505922 , have been associated with TNF-alpha levels.[1]Investigating these genetic influences provides valuable insights into individual differences in protein regulation and metabolism, potentially contributing to more personalized health assessments and disease prevention strategies.
Limitations in Generalizability and Population Diversity
Section titled “Limitations in Generalizability and Population Diversity”The current understanding of total blood protein concentrations, while advanced by transethnic meta-analysis, faces significant limitations regarding its generalizability across diverse populations. Studies have revealed strong evidence of heterogeneity, such as at theARID5B locus for total protein, where the lead SNP rs2675609 showed a robust association exclusively in the Japanese GWAS, with allelic effects in opposite directions when compared to the European meta-analysis.[2] This indicates that genetic associations and their impacts on total protein levels can vary substantially between ancestry groups, limiting the direct applicability of findings to populations not well-represented in current research. Furthermore, a considerable portion of the large-scale genomic analyses, including those from the UK Biobank, have predominantly focused on participants of European or British ancestry.[3] This demographic imbalance can introduce cohort bias and restricts the broader generalizability of identified genetic variants and their effect sizes to a global population.
Phenotypic Definition and Environmental Confounding
Section titled “Phenotypic Definition and Environmental Confounding”Another key limitation stems from the composite nature of “total blood protein” as a phenotype, which inherently lumps together numerous individual proteins without specific differentiation. For instance, intrastudy phenotypic variation in specific protein components, such as immunoglobulin (Ig) concentrations, which were often unavailable for analysis, could contribute to observed transethnic differences in allelic effects, thereby obscuring more granular biological insights.[2]This broad can mask the distinct genetic and environmental factors influencing various protein fractions, making it challenging to identify precise molecular pathways. Moreover, total blood protein levels are susceptible to numerous environmental and technical confounders; researchers frequently adjust for factors like age, sex, smoking status, collection site, batch effects, and the time interval between blood sampling and protein.[3] Despite these rigorous adjustments, the potential for residual confounding from unmeasured environmental exposures or complex gene-environment interactions remains, which could still influence observed genetic associations and complicate their accurate interpretation.
Statistical Power and Unresolved Genetic Architecture
Section titled “Statistical Power and Unresolved Genetic Architecture”Despite the utilization of large cohorts and advanced statistical methods like transethnic meta-analysis, research into total blood protein still contends with limitations in statistical power, particularly for the discovery of novel or rarer genetic variants. Studies suggest that additional sequence variants could be identified with even larger sample sizes and improved statistical power for gene discovery, implying that the current understanding represents only an initial, partial elucidation of the complex genetic architecture underlying total blood protein concentrations.[4] While valuable initial insights into the genetic underpinnings have been provided, significant knowledge gaps persist regarding the full spectrum of genetic influences and the precise molecular mechanisms driving observed associations.[2] Specifically, further investigation is required to fully elucidate the sources of heterogeneity observed between different ancestry groups, highlighting that the intricate interplay of genetic and environmental factors across diverse human populations is not yet completely understood.
Variants
Section titled “Variants”The genetic variations influencing total blood protein levels are diverse, spanning genes involved in immune function, metabolic regulation, and protein processing. These variants can alter the expression, activity, or stability of proteins, thereby affecting their concentration in the bloodstream. Understanding these genetic influences provides insight into individual differences in health and disease susceptibility.
Genes like FCGR3B and FCGR2B encode Fc gamma receptors, which are crucial components of the immune system that bind to the Fc portion of antibodies, particularly IgG. Variants such as rs2926468 and rs1771582 are associated with these receptors and can influence their expression levels or binding affinities, thereby altering immune complex clearance and cellular activation. These variations may consequently impact the circulating levels of immunoglobulins or other immune-related proteins, reflecting individual differences in immune surveillance and inflammatory responses . Similarly, the FCGRT gene (Fc Fragment of IgG Receptor and Transporter) is essential for regulating IgG and albumin levels by preventing their degradation and ensuring prolonged circulation. Variants like rs142385484 , rs150420714 , and rs62128087 within FCGRTcan affect its efficiency in IgG and albumin recycling, directly influencing total blood protein concentrations and potentially impacting immune-mediated conditions. TheHLA-DQB1 gene, represented by rs9274442 , is a crucial part of the Major Histocompatibility Complex (MHC) class II, central to presenting antigens to T-cells and initiating adaptive immune responses. Polymorphisms in HLA-DQB1 can alter the range of peptides presented, affecting immune tolerance and the production of specific antibodies and cytokines, which collectively contribute to the total protein profile in blood .
Variations in genes such as TNFRSF13B, TNFSF13, TNFSF12-TNFSF13, and TRAF3 play significant roles in B cell biology and immune signaling. TNFRSF13B encodes TACI (Transmembrane Activator and CAML Interactor), a receptor on B cells vital for their survival, proliferation, and antibody production through binding to BAFF and APRIL. Variants such as rs34562254 , rs34557412 , and rs4561508 in TNFRSF13B can affect TACI signaling, potentially leading to altered immunoglobulin levels and influencing the overall protein composition of blood plasma . TRAF3 (TNF Receptor Associated Factor 3) is an adapter protein mediating signaling from various TNF receptors, critical for regulating B cell survival and antibody class switching. The variants rs12880641 , rs12436513 , and rs35919282 in TRAF3 may modify these pathways, contributing to variations in immune protein levels. Furthermore, TNFSF13 (APRIL) and the linked TNFSF12-TNFSF13 locus, with variant rs3803800 , are key ligands for TACI and BCMA receptors, promoting B cell maturation and survival. Alterations in these genes, particularly affecting ligand availability or receptor interaction, can lead to dysregulation of B cell responses and subsequent changes in circulating antibody and cytokine concentrations .
Other genes contribute to total blood protein through metabolic regulation and cellular protein handling. Thers1260326 variant in the GCKRgene, encoding Glucokinase Regulatory Protein, is crucial for regulating glucokinase activity in the liver, a process fundamental to glucose metabolism. This regulation indirectly impacts lipid and protein synthesis pathways in the liver, a primary site for plasma protein production. Variations inGCKR can thus affect metabolic profiles and potentially influence the synthesis of various circulating proteins, including those involved in nutrient transport and inflammation . The SERPINA1 gene encodes alpha-1 antitrypsin, a major plasma protein synthesized in the liver that protects tissues from enzyme degradation. Deficiencies or functional alterations caused by variants like rs28929474 , rs28929470 , and rs17580 can lead to severe lung and liver diseases, directly impacting total blood protein levels and the balance of protective proteins in circulation.SNX8 (Sorting Nexin 8), with variant rs144787122 , is involved in endosomal sorting and trafficking, processes essential for the proper handling and secretion of many cellular proteins. While its direct impact on total blood protein is less prominent, efficient protein trafficking is fundamental for maintaining cellular function and indirectly contributes to the overall protein secretome.RPL31P11, a pseudogene associated with rs10917688 , is a non-coding DNA sequence related to the ribosomal protein L31. Although pseudogenes typically do not encode functional proteins, they can sometimes influence gene expression through various regulatory mechanisms, potentially having subtle, indirect effects on protein synthesis or cellular processes that contribute to the overall blood protein landscape .
Key Variants
Section titled “Key Variants”| RS ID | Gene | Related Traits |
|---|---|---|
| rs2926468 rs1771582 | FCGR3B - FCGR2B | MANSC domain-containing protein 1 total blood protein neurogenic locus notch homolog protein 1 level of podocalyxin-like protein 2 in blood |
| rs34562254 rs34557412 rs4561508 | TNFRSF13B | multiple myeloma serum albumin amount sodium FCRL5/TNFRSF13B protein level ratio in blood CD27/DLL1 protein level ratio in blood |
| rs9274442 | HLA-DQB1 | total blood protein platelet glycoprotein 4 level plasma plasminogen |
| rs142385484 rs150420714 rs62128087 | FCGRT | protein triglyceride total cholesterol low density lipoprotein cholesterol aspartate aminotransferase |
| rs10917688 | RPL31P11, RPL31P11 | total blood protein |
| rs12880641 rs12436513 rs35919282 | TRAF3 | CD27 antigen level of immunoglobulin lambda constant 2 (human) in blood total blood protein hip circumference CD5 antigen-like |
| rs1260326 | GCKR | urate total blood protein serum albumin amount coronary artery calcification lipid |
| rs3803800 | TNFSF13, TNFSF12-TNFSF13 | level of serum globulin type protein IGA glomerulonephritis albumin:globulin ratio serum IgA amount serum albumin amount |
| rs144787122 | SNX8 | serum albumin amount total cholesterol aspartate aminotransferase heel bone mineral density apolipoprotein B |
| rs28929474 rs28929470 rs17580 | SERPINA1 | forced expiratory volume, response to bronchodilator FEV/FVC ratio, response to bronchodilator alcohol consumption quality heel bone mineral density serum alanine aminotransferase amount |
Causes of Total Blood Protein Variation
Section titled “Causes of Total Blood Protein Variation”Total blood protein, a composite measure of various proteins circulating in the plasma, is influenced by a complex interplay of genetic, environmental, and systemic factors. Variations in its levels can reflect underlying physiological states, disease processes, or responses to external stimuli.
Genetic Predisposition
Section titled “Genetic Predisposition”Genetic factors significantly contribute to individual differences in total blood protein levels by influencing the synthesis, degradation, and regulation of constituent proteins. Genome-wide association studies (GWAS) have been instrumental in identifying genetic variants that affect quantitative traits, including the levels of specific proteins found in blood. For instance, the Framingham Heart Study has served as a valuable resource for identifying such genetic associations across various phenotypes.[5]While total blood protein itself is a polygenic trait, specific inherited variants can have measurable impacts on individual protein components, thereby contributing to overall protein concentration.
Polymorphisms within certain genes can directly alter the expression or function of specific proteins. For example, polymorphisms in the HNF1A, a gene encoding hepatocyte nuclear factor-1 alpha, have been found to be associated with C-reactive protein levels.[6]C-reactive protein is an acute-phase protein that contributes to the total protein pool, illustrating how genetic variations in regulatory genes can affect the concentration of specific blood proteins. Similarly, genetic factors influence the activity and mass of enzymes like Lp-PLA.[7] another protein circulating in the blood, as revealed by genome-wide association studies.[8]
Environmental and Lifestyle Influences
Section titled “Environmental and Lifestyle Influences”External factors, including lifestyle choices, diet, and therapeutic interventions, can significantly modulate total blood protein levels. These environmental elements can impact protein synthesis in organs like the liver, influence protein catabolism, or affect the body’s inflammatory response, thereby altering the circulating protein profile. For instance, medication effects represent a direct environmental influence on blood protein concentrations.
Statin therapy, commonly used to manage cholesterol levels, has been observed to affect C-reactive protein levels.[9]Since C-reactive protein is a component of total blood protein, such pharmacological interventions demonstrate how external agents can influence the overall protein by specifically altering the levels of individual proteins within the blood. The body’s response to various exposures and lifestyle factors, although not explicitly detailed for total blood protein in this context, broadly impacts metabolic and inflammatory pathways that govern protein dynamics.
Complex Interactions and Modulating Factors
Section titled “Complex Interactions and Modulating Factors”The regulation of total blood protein is not solely determined by isolated genetic or environmental factors but often arises from their intricate interactions. A genetic predisposition to certain protein levels can be significantly modified by environmental triggers or therapeutic interventions, leading to a dynamic range of total protein measurements. For example, individuals with specific genetic variants that influence C-reactive protein levels may experience different magnitudes of response to statin therapy compared to those with other genotypes, illustrating a gene-environment interaction.
This interplay means that while a genetic profile might set a baseline for protein production, factors such as medication use can modulate these levels, either increasing or decreasing the concentration of specific proteins that contribute to the total.[6]
Biological Background
Section titled “Biological Background”Total blood protein refers to the sum of all proteins found in the plasma portion of blood, playing crucial roles in maintaining physiological balance, transport, immunity, and coagulation. The intricate balance of these proteins is maintained through complex molecular, cellular, and genetic mechanisms, and their levels serve as important indicators of overall health and disease states. Variations in total blood protein can reflect alterations in synthesis, degradation, or distribution of individual protein components, impacting systemic functions.
Proteins in Blood Function and Hemostasis
Section titled “Proteins in Blood Function and Hemostasis”Blood plasma contains a diverse array of proteins, each with specialized functions critical for maintaining bodily homeostasis. Key among these are proteins involved in hemostasis, the process of preventing and stopping bleeding. For instance, fibrinogen is a vital plasma protein that plays a central role in blood coagulation, forming the fibrin clot necessary for wound healing . These genetic predispositions dictate the transcription and translation rates of genes encoding specific proteins, thereby regulating their synthesis. For instance, the production of essential proteins like fibrinogen, a critical component in coagulation, is under such genetic control, ensuring its availability within the blood plasma.[10] This intricate gene regulation forms the initial layer of control over the protein composition of blood.
Signaling Cascades in Cellular Function
Section titled “Signaling Cascades in Cellular Function”Specific blood protein components are dynamically regulated through complex signaling cascades that mediate cellular responses. An example involves the aggregation of blood platelets, a process crucial for hemostasis, which is initiated by molecules such as adenosine diphosphate (ADP).[7] This activation involves receptor binding on the platelet surface, triggering intracellular signaling pathways that lead to changes in protein conformation and activity, ultimately promoting platelet-platelet adhesion. The subsequent reversal of this aggregation also involves specific signaling mechanisms that deactivate the platelets, highlighting the tight control over protein function in response to environmental cues.[7]
Post-Translational Modification and Metabolic Homeostasis
Section titled “Post-Translational Modification and Metabolic Homeostasis”Beyond initial synthesis, the functional activity and lifespan of blood proteins are further controlled by post-translational modifications and metabolic processes. While not explicitly detailed in the provided studies, the existence of diverse hemostatic factors implies a continuous cycle of protein synthesis, modification, and catabolism to maintain physiological balance.[11] These modifications, such as phosphorylation or glycosylation, can alter protein structure, stability, localization, and interaction partners, fine-tuning their roles in complex biological pathways. Maintaining the appropriate balance of these circulating proteins is a key aspect of metabolic homeostasis, ensuring their availability for critical functions while allowing for their degradation when no longer needed.
Systems-Level Integration and Disease Relevance
Section titled “Systems-Level Integration and Disease Relevance”The various pathways governing blood protein levels and functions do not operate in isolation but are intricately interconnected, forming a highly integrated biological network. This systems-level integration is crucial for maintaining overall physiological balance, where alterations in one pathway can profoundly impact others and influence emergent properties of the blood system.[11]For example, dysregulation within these networks can lead to pathological states, as observed in the association between obesity and a prothrombotic state.[12]This highlights how metabolic imbalances, potentially affecting the synthesis, modification, or degradation of multiple blood proteins, can contribute to disease mechanisms and represent potential therapeutic targets.
Role in Liver Function Assessment and Diagnostics
Section titled “Role in Liver Function Assessment and Diagnostics”Total blood protein, specifically serum total protein, serves as a crucial parameter in the comprehensive assessment of liver function and associated diagnostic pathways. Its inclusion as an adjustment factor in multivariable models for liver enzymes such as aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and gamma-glutamyl transferase underscores its importance in understanding the overall physiological state of the liver.[13]Abnormal levels of serum total protein can signal underlying hepatic dysfunction or disease, guiding clinicians in further diagnostic investigations to identify the specific etiology.
The integration of serum total protein into complex analytical models, alongside other significant variables like age, sex, body mass index (BMI), high-density lipoprotein (HDL) cholesterol, hypertension, diabetes, alcohol intake, triglycerides, and smoking, enhances the diagnostic utility of liver biomarker panels.[13] This comprehensive approach allows for a more nuanced interpretation of liver enzyme levels, enabling clinicians to discern primary liver pathologies from conditions where protein metabolism is broadly affected, thereby contributing to more accurate diagnoses and informed clinical decision-making.
Associations with Comorbidities and Systemic Risk Factors
Section titled “Associations with Comorbidities and Systemic Risk Factors”Serum total protein levels are intricately associated with a spectrum of comorbidities and systemic risk factors, reflecting its role as a general indicator of health status. Its consideration as an adjustment variable alongside conditions such as diabetes and hypertension, as well as lifestyle factors like alcohol intake and smoking, highlights its interconnectedness with broader metabolic and cardiovascular health.[13] This suggests that variations in serum total protein may not only indicate liver-specific issues but also reflect the impact of these systemic conditions on protein synthesis, degradation, or overall nutritional status.
By accounting for serum total protein when evaluating liver function biomarkers, clinicians acknowledge its potential to act as an indirect marker for the interplay between various comorbidities and organ health. This integrated perspective is vital for identifying individuals with complex overlapping phenotypes, where liver health may be compromised by multiple concurrent systemic issues, facilitating a more holistic understanding of patient risk profiles and disease mechanisms.
Implications for Risk Stratification and Prognosis
Section titled “Implications for Risk Stratification and Prognosis”While not a standalone prognostic marker in the context provided, the role of serum total protein in multivariable models for liver function biomarkers suggests an indirect yet significant contribution to risk stratification for liver-related complications and overall patient outcomes. By refining the assessment of liver health when considered alongside other clinical and demographic factors, serum total protein can aid in identifying individuals at a higher risk for adverse events related to hepatic dysfunction.[13] This enhanced risk assessment is crucial for tailoring individualized management plans.
Understanding serum total protein levels, particularly in conjunction with a patient’s complete clinical picture and lifestyle attributes, supports a more personalized approach to patient care. This comprehensive evaluation refines disease risk assessment and can inform the development of targeted prevention strategies, ultimately contributing to improved long-term health outcomes in conditions where liver function is a critical determinant of disease progression and overall prognosis.
Frequently Asked Questions About Total Blood Protein
Section titled “Frequently Asked Questions About Total Blood Protein”These questions address the most important and specific aspects of total blood protein based on current genetic research.
1. My sibling has high protein, but mine is normal. Why the difference?
Section titled “1. My sibling has high protein, but mine is normal. Why the difference?”Even within families, individual protein levels can vary due to unique genetic variations. While some factors are shared, specific genetic predispositions inherited from your parents can influence how your body produces, processes, or loses proteins differently, even if you share a similar environment.
2. Does my ethnic background affect what my “normal” protein levels should be?
Section titled “2. Does my ethnic background affect what my “normal” protein levels should be?”Yes, research shows that genetic associations with total blood protein levels can differ significantly between ancestry groups. What’s considered typical or a risk factor in one population might not be the same in another, highlighting the importance of diverse research.
3. If I’m not drinking enough water, will my protein levels look off?
Section titled “3. If I’m not drinking enough water, will my protein levels look off?”Absolutely. Dehydration is a common reason for elevated total blood protein levels. When you have less fluid in your blood, the concentration of proteins appears higher, even if the absolute amount hasn’t changed.
4. Does eating poorly for a while actually make my protein levels drop?
Section titled “4. Does eating poorly for a while actually make my protein levels drop?”Yes, prolonged poor nutrition or malnutrition can lead to low total blood protein levels. Your body needs adequate nutrients to synthesize essential proteins like albumin, and a lack of these can impair production.
5. My friend eats everything, but their protein levels are fine. Why might mine be different?
Section titled “5. My friend eats everything, but their protein levels are fine. Why might mine be different?”Individual differences in protein levels, even with similar lifestyles, can be influenced by your unique genetic makeup. Genetic variations affect how your body regulates protein production, breakdown, and transport, leading to varying baseline levels among people.
6. Does my age affect what my doctor considers a normal protein level?
Section titled “6. Does my age affect what my doctor considers a normal protein level?”Yes, age is one of several factors that doctors and researchers account for when interpreting total blood protein levels. These levels can fluctuate throughout life, and what’s considered normal can vary by age group.
7. Can stress or long-term inflammation make my protein levels abnormal?
Section titled “7. Can stress or long-term inflammation make my protein levels abnormal?”Yes, chronic inflammation, which can be exacerbated by stress, often leads to elevated total blood protein levels. This is because inflammation can trigger an increase in certain globulin proteins, like antibodies, as your body responds to the perceived threat.
8. If my liver or kidneys aren’t working great, would my protein levels show that?
Section titled “8. If my liver or kidneys aren’t working great, would my protein levels show that?”Absolutely. Your liver is crucial for making many blood proteins, like albumin, and your kidneys help retain them. Problems with either organ, such as severe liver dysfunction or kidney disease, can significantly impact your total blood protein levels.
9. My doctor keeps checking my protein levels. What important things does this test tell them about me?
Section titled “9. My doctor keeps checking my protein levels. What important things does this test tell them about me?”This test provides crucial insights into your nutritional status, how well your organs (like liver and kidneys) are functioning, and if there are any inflammatory or immune system disorders present. It helps guide further diagnostic investigations.
10. Could a DNA test tell me why my protein levels are often high or low?
Section titled “10. Could a DNA test tell me why my protein levels are often high or low?”Potentially, yes. Research into protein quantitative trait loci (pQTLs) identifies specific genetic regions linked to variations in protein concentrations. A DNA test could reveal genetic predispositions that influence your individual protein regulation and metabolism.
This FAQ was automatically generated based on current genetic research and may be updated as new information becomes available.
Disclaimer: This information is for educational purposes only and should not be used as a substitute for professional medical advice. Always consult with a healthcare provider for personalized medical guidance.
References
Section titled “References”[1] Melzer, D., et al. “A Genome-Wide Association Study Identifies Protein Quantitative Trait Loci (pQTLs).” PLoS Genetics, vol. 4, no. 5, 2008, p. e1000072.
[2] Franceschini, N. et al. “Discovery and fine mapping of serum protein loci through transethnic meta-analysis.” American Journal of Human Genetics, 2012.
[3] Loya, H. et al. “A scalable variational inference approach for increased mixed-model association power.” Nature Genetics.
[4] Kathiresan, S. et al. “Common variants at 30 loci contribute to polygenic dyslipidemia.” Nature Genetics.
[5] Cupples, L. A., et al. “The Framingham Heart Study 100K SNP genome-wide association study resource: overview of 17 phenotype working group reports.” BMC Med Genet, 2007, 8 Suppl 1: S1.
[6] Reiner, A. P., et al. “Polymorphisms of the HNF1A gene encoding hepatocyte nuclear factor-1 alpha are associated with C-reactive protein.”Am J Hum Genet, 2008, 82.
[7] Born, G. V. R. “Aggregation of Blood Platelets by Adenosine Diphosphate and its Reversal.”Nature, vol. 194, 1962, pp. 927-929.
[8] Suchindran, S., et al. “Genome-wide association study of Lp-PLA(2) activity and mass in the Framingham Heart Study.” PLoS Genet, 2010, PMID: 20442857.
[9] Investigators. “Effect of statin therapy on C-reactive protein levels: the pravastatin inflammation/CRP evaluation (PRINCE): a randomized trial and cohort study.”JAMA, 2001, 286.
[10] Clauss, A. “[Rapid physiological coagulation method in determination of fibrinogen].” Acta Haematol, vol. 17, 1957, pp. 237-246.
[11] Yang, Q., et al. “Genome-wide association and linkage analyses of hemostatic factors and hematological phenotypes in the Framingham Heart Study.”BMC Med Genet, vol. 8, 2007.
[12] Rosito, G. A., et al. “Association between obesity and a prothrombotic state: the Framingham Offspring Study.”Thromb Haemost, vol. 91, 2004, pp. 683-689.
[13] Benjamin, Emelia J., et al. “Genome-wide association with select biomarker traits in the Framingham Heart Study.” BMC Medical Genetics, vol. 8, 2007, p. 74.